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Clark returns to Smallville as Kal-El - intent on fulfilling his destiny, he goes after a powerful kryptonian crystal that Lex has obtained in Egypt. Meanwhile, newcomer Lois Lane arrives in Smallville to look into the death of her cousin Chloe, and Lana returns from Paris with a new boyfriend. Jonathan lies in a coma after the events of last year's season finale and Lionel must deal with his new life in prison.

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After discovering that Chloe's body isn't in her coffin, Clark and Lois Lane investigate but are stopped by Lois' father, General Sam Lane. They believe General Lane knows more then he's telling, and figure out he's been in contact with Lex. Meanwhile, after Lana's sudden departure Jason follows her to Smallville. And Lionel sends a mutant killer to determine if Chloe is alive and kill her for sure.

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Abigail, an ugly high school girl, gets plastic surgery from her surgeon-mother to boost her popularity. However, her beauty hides a dark secret - when she kisses someone they're inflicted with life-threatening hallucinations. When Lana sees Abigail with one of her victims, she becomes the next target.

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Clark decides to join the football team over Jonathan's wishes and gets the starting quarterback position when his predecessor attacks Jason over a girl. Clark and Lois investigate and discover that the cheerleaders are using kryptontie in the team's water supply to turn them into obedient mindless boyfriends.

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Jonathan's wallet is stolen by a super-speed thief, Bart Allen, who is faster then Clark. Bart comes to the farm and becomes friends with Clark, but Bart returns to crime when he sees an ancient manuscript that Lex has. As Clark soon realizes, the manuscript holds a map to one of the kryptonian crystals and he must go up against Bart to recover it.

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Clark is drawn to the state penitentery by one of the kryptonian crystals, which Lionel is using to switch bodies with Lex. Clark intervenes and Lionel enters his body instead. While Lionel uses his newfound super-powers to regain his lost fortune and alienate Clark's friend, Clark must convince his parents that he is the "real" Clark and reverse the processs, while avoiding murderous convicts.

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Mikail Mxyzptlk, a foreign exchange student and bookie, has the power to control others and uses it to sabotage football games, including the one Clark is quarterbacking. Clark and Chloe figure out his secret, but he threatens to kill Chloe unless Clark throws the next game. Mikail came to Smallville via LuthorCorp, and Lex will do almost anything to learn his secret.

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Lana reads a spell book belonging to her 17th century ancestor, the witch Isabelle, and becomes possessed by her spirit. Isabelle resurrects her other two witches and together they seek out the kryptonian crystals, using their magic to render Clark powerless.

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Lex is accused of killing a young woman and Clark turns to Lionel for help. Meanwhile, Lana has a dream of her ancestor and a mysterious second woman - a dead ringer for Jason's mother Genevieve, who arrives to visit her son and his new girlfriend.

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A Luthorcorp experiment is released into the atmosphere - a toxin that causes its victims to hallucinate their worst fear. Chloe, Clark, Lana, and Jason all fall fictim to the toxin, and Lex, desperate to find a cure, takes a dangerous antidote. Meanwhile, Lionel is released from prison and his conviction overturned thanks to a mysterious benefactor.